tbuckley/cabot-search huggingface dataset:
Abstract B012: Differential stress responses drive asparagine exchange in pancreatic cancer
Authors: Cecily Anaraki, Galloway Thurston, Nina G. Steele, Samuel A. Kerk, Hanna Hong, Peter Sajjakulnukit, Anthony Andren, Catherine Felton, Alica Beutel, Rima Singh, Heather R. Christofk, Andrea Viale, Howard Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A. Lyssiotis, Christopher J. Halbrook
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, contrasting a relatively low incidence rate. A principal barrier to the treatment of pancreatic cancer is the densely fibrotic tumor microenvironment and the high interstitial pressure which acts to collapse blood vessels, impairing the delivery of chemotherapy. This lack of functional vasculature limits nutrient availability within the tumor, causing cancer cells to develop numerous metabolic adaptations to allow for proliferation in hypoxic, austere conditions. Recent studies have demonstrated several clonal behaviors of cancer cells within individual pancreatic tumors, although it is unclear if this is true of metabolism. Exploring this, we found the metabolic profiles and sensitivities of a series of clonal cell lines derived from a single pancreatic tumor clustered into two distinct groups. These groups demonstrated differential sensitivities to inhibitors of mitochondrial metabolism; whereby the growth of the sensitive clones during impaired respiration can be rescued through co-culture with the insensitive cells. Profiling metabolites exchanged by the clonal populations, we identified this is mediated by asparagine released by insensitive cells. Mechanistically, the production of asparagine is driven by differential stress response pathway activation between clones. We further determined that exogenous asparagine supports the growth of both cancer and non-cancerous cells during limited respiration. Conversely, we found that the use of asparaginase to degrade asparagine sensitizes PDA tumors to mitochondrial inhibition. Collectively these data demonstrate distinct metabolic classes of cancer cells within single tumors and identify asparagine as a potential target to sensitize tumors to mitochondrial inhibition. Citation Format: Cecily Anaraki, Galloway Thurston, Nina G. Steele, Samuel A. Kerk, Hanna Hong, Peter Sajjakulnukit, Anthony Andren, Catherine Felton, Alica Beutel, Rima Singh, Heather R. Christofk, Andrea Viale, Howard Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A. Lyssiotis, Christopher J. Halbrook. Differential stress responses drive asparagine exchange in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B012.
Abstract A066: 5z-7-oxozeaenol as an epithelial mesenchymal transition plasticity inhibitor in PDAC
Authors: Eunae You, Ildiko Phillips E. Phillips, Richard Y. Ebright, Niyati Desai, Michael J. Raabe, Evan R. Lang, Linda T. Nieman, Soroush Hajizadeh, Johannes Kreuzer, Wilhelm Haas, David T. Ting
Journal: Cancer Research (2022)

Abstract Transcriptional profiling has defined PDAC into distinct classical epithelial (E) or quasi-mesenchymal (QM) subtypes, and these subtypes exist on a continuum of interconverting cell states. This epithelial to mesenchymal transition (EMT) plasticity is thought to be important for the metastatic dissemination and intrinsic resistance to chemotherapy. Our prior work identified TAK1 as an important driver of EMT in mouse circulating tumor cells, and we had identified a compound (5z)-7-oxozeaenol (Oxo) as a small molecule inhibitor of TAK1. Here, we have expanded upon this prior work by evaluating Oxo in 3 human patient derived PDAC cell lines as an EMT plasticity inhibitor. Treatment with Oxo induced a shift of all PDAC cell lines towards an E phenotype in both E and QM PDAC cell lines using RNA-seq and quantitative RNA in situ hybridization. This was associated with increased FFX sensitivity, loss of migratory abilities of all cell lines by Boyden chamber, and decreased invasion in matrigel. Interestingly, genetic TAK1 knockout via CRISPR/Cas9 in these PDAC cell lines showed different effects from Oxo. We found that TAK1 knockout decreased E PDAC cell line migratory behavior and increased FFX sensitivity, but QM PDAC cell lines were not affected by TAK1 knockout. This suggests that QM PDAC cell lines have additional signaling cascades that compensate for TAK1 loss and that Oxo effects across PDAC cell lines are not solely TAK1 dependent. Using phospho-proteomics, in FFX treated PDAC cell lines, we have identified potential candidate pathways in RNA splicing and viral processes that may be additional processes affected by Oxo that merits further investigation. Altogether, we have identified Oxo as a potential broad EMT plasticity inhibitor across PDAC subtypes, and there is a potential role of selective TAK1 inhibitors for E PDAC tumors. Citation Format: Eunae You, Ildiko Phillips E. Phillips, Richard Y. Ebright, Niyati Desai, Michael J. Raabe, Evan R. Lang, Linda T. Nieman, Soroush Hajizadeh, Johannes Kreuzer, Wilhelm Haas, David T. Ting. 5z-7-oxozeaenol as an epithelial mesenchymal transition plasticity inhibitor in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A066.
Abstract C074: Mining the secreted microproteome for novel regulators of PDAC progression
Authors: Marion Martinez, Marta Hergueta, Pilar Ximénez de Embún, Ana Dueso, David Torrents, Teresa Macarulla, Javier Muñoz, Héctor Peinado, María Abad
Journal: Cancer Research (2022)

Abstract Recent work has unveiled a hidden microproteome composed by thousands of small proteins named microproteins: they are functional short proteins coded by genomic regions previously considered non-coding, and which had been completely ignored, mainly due to their small size (&amp;lt;100 aminoacids). To date, only a small part of the thousands of microproteins present in our cells have been characterized, and they are key players in fundamental processes such as DNA repair, mRNA splicing or cell metabolism. In cancer, they have been shown to regulate most tumor hallmarks, and present a huge potential for the clinic as diagnostic and prognostic biomarkers as well as therapeutic targets. Interestingly, their small size makes them ideal candidates to be shed in tumor-derived exosomes. PDAC-shed exosomes have been shown to prepare the pre-metastatic niche in the liver, and their presence in the bloodstream can be used as a surrogate marker of metastasis. Herein, we have mined the PDAC exosome-secreted microproteome for novel regulators of tumor progression and metastasis. Using proteogenomics in PDAC patient-derived explants, we have identified 439 microproteins secreted in exosomes by pancreatic tumors. We have selected a set of top microprotein candidates for further characterization by in silico analyses (e.g. phylogenetic conservation, predicted protein stability and localisation, mRNA expression in PDAC, etc). We have confirmed their exosome secretion in PDAC cell lines, and preliminary characterisation of these top candidates has shown that they extrinsically promote PDAC cell growth and invasion in vitro. Together, this work advances our knowledge on the underexplored field of secreted microproteins and provides pioneering evidence of their role in tumor cell communication in PDAC. It may further be a source of novel therapeutic targets and PDAC biomarkers for liquid biopsy in the clinic. Citation Format: Marion Martinez, Marta Hergueta, Pilar Ximénez de Embún, Ana Dueso, David Torrents, Teresa Macarulla, Javier Muñoz, Héctor Peinado, María Abad. Mining the secreted microproteome for novel regulators of PDAC progression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C074.
Abstract B067: Genetic and pharmacological inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice
Authors: Hala A. Addassi, Gerardo G. Mackenzie
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related death in the United States and is characterized by its sudden manifestation, poor prognosis, high incidence of metastasis, and aggressive tumor growth. Phospholipase D1 (PLD1) is a lipid-signaling enzyme that plays a role in signaling pathways that lead to cell proliferation, survival/apoptosis as well as downstream oncogenic transformation involved in cancer progression. PLD1 activity has been shown to promote tumor progression in other cancer types, however, the role and mechanisms of PLD1 in pancreatic cancer is not yet understood. The objective of this study is to determine the role of PLD1 regulation in pancreatic carcinogenesis through genetic-ablation and pharmacological inhibition of PLD1. In this study, we crossed the LSL-KrasG12D/+;Ptf1Cre/+ (KC) mice into PLD1 knockout (Pld1-/-) mice to generate KC; Pld1-/- mice in the C57BL/6 background to examine whether PLD1 is required for pancreatic tumorigenesis. Cohorts of male and female KC and KC; Pld1-/- mice, (8-12 mice per group), were euthanized at 4 and 8 months old and the pancreas was carefully resected. At 8 months of age, there was a significant difference (p&amp;lt;0.05) in the pancreas weight at sacrifice between the KC mice and the KC; Pld1-/- mice in a sex-dependent manner. This was due, in part, by a reduction in tumor proliferation as determined by Ki67 expression. To assess whether pharmacological inhibition of PLD could prevent pancreatic carcinogenesis in KC mice, cohorts of 9-12 male 7-month-old KC mice received daily intraperitoneal injections of a small molecule inhibitor of PLD (FIPI) at a dosage of 3 mg/kg of body weight for a duration of 5 weeks. The mice were euthanized at 8.5 months of age and the pancreas was carefully resected. Histological analysis indicated that FIPI-treated KC mice displayed less acinar cell loss compared to vehicle-treated KC controls. Moreover, treatment with FIPI significantly reduced cell proliferation (p&amp;lt;0.01) in KC mice in comparison to vehicle-treated KC mice. In summary, these results indicate that PLD1 plays a critical role in pancreatic carcinogenesis and may represent a novel therapeutic target. Additional studies are underway to explore the cellular mechanisms of how PLD1 inhibition modulates pancreatic carcinogenesis. Citation Format: Hala A. Addassi, Gerardo G. Mackenzie. Genetic and pharmacological inhibition of phospholipase D1 reduces pancreatic carcinogenesis in mice [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B067.
Abstract IA018: ATP production in pancreas cancer and tumor infiltrating lymphocytes
Authors: Joshua D. Rabinowitz
Journal: Cancer Research (2022)

Abstract Diet can influence both the microbiome and (at least in mice) the outcomes of pancreas cancer therapy. For example, ketogenic diet can synergize with either current standard of care therapy ( gemcitabine + nab-paclitaxel) or PI3K inhibition in mouse models of pancreas cancer. I will discuss our recent work exploring how diet interacts with the microbiome, and how such interactions may influence pancreas cancer chemotherapy response. A simple hypothesis for how diet influences microbiome composition is that certain microbes prefer certain nutrients, and diets high in those nutrients lead to outgrowth of those microbes. To enable testing of this hypothesis, we developed isotope-tracer strategies that directly measure the nutrient preferences of different members of the gut microbiome. I will describe this new technology and its application to support the above hypothesis. I will further describe experiments manipulating diet and/or microbiome to influence the response of pancreas cancer to PI3K inhibition. The longterm goal is to understand, at a biochemical level, the links between diet, microbiome, and the effectiveness of cancer therapy, and to develop translatable strategies for manipulating metabolism via diet to improve therapeutic outcomes. Citation Format: Joshua D. Rabinowitz. ATP production in pancreas cancer and tumor infiltrating lymphocytes [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA018.
Abstract A024: Prognostic effects of different TP53 mutations in pancreatic ductal adenocarcinoma
Authors: Carlos M. Mejia Arbelaez, Xining Shan, Tseng Robert, Marie E. Robert, Xiaomei Ma, Luisa F. Escobar-Hoyos
Journal: Cancer Research (2022)

Abstract Approximately, 70% of pancreatic ductal adenocarcinomas (PDACs) have mutations in the TP53 gene; however, it is still unknown if gain- or loss- of function mutations in TP53 provide differential prognostic value to guide therapy. To fill this gap, we assessed the potential effect of wild-type, missense (gain-of-function) and truncating (loss-of-function) TP53 mutations in patient survival, in two independent clinical cohorts (The Cancer Genome Atlas cohort=141, and the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets cohort=376 PDACs). We employed multivariable Cox proportional hazards regression models adjusting for patient demographic (age at diagnosis, sex, race/ethnicity) and tumor characteristics (presence of distant metastasis at diagnosis). Additionally, we conducted stratified analyses by the status of “druggable” (DNA repair gene mutations) and other driver mutations (SMAD4 and CDKN2A genes). We found that PDACs with missense TP53 mutations were associated with a worse patient survival compared to tumors with wild-typeTP53 (HR = 1.47, 95% CI: 1.00-2.17; p=0.051). Similarly, patients with truncating mutations in TP53 had a trend to worse OS (HR=1.11, 95% CI, 0.70-1.76; p=0.654) compared to patients with wild-type TP53, however, these associations were not significant. Furthermore, we found that mutations in DNA repair genes, SMAD4 and CDKN2A genes did not show any prognostic value. Our findings suggest that molecular characterization of specific TP53 mutations may help to determine differences in patient prognosis and potentially guide future clinical management of patients. Citation Format: Carlos M. Mejia Arbelaez, Xining Shan, Tseng Robert, Marie E. Robert, Xiaomei Ma, Luisa F. Escobar-Hoyos. Prognostic effects of different TP53 mutations in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A024.
Abstract C072: Cytokine modulation can suppress an EMT-like phenotype in pancreatic cancer
Authors: Whitney Bell, Nancy Kren, Yan Wang, Yuliya Pylayeva-Gupta
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate of only 11% and approximately half of patients present with distant metastasis at the time of diagnosis. PDAC is accompanied by pronounced alterations in stromal responses and immune surveillance programs, which are now recognized as some of the major drivers in PDAC tumor evolution. The role of immune modulators in driving metastatic potential in PDAC is poorly understood. We find that low expression levels of cytokine IL-23 in patients with PDAC correlate with poor differentiation status of these tumors, and thus predict poor outcomes. Consistent with this observation, we have found that a loss of host-derived IL-23 in a mouse model of pancreatic cancer promotes an EMT-like phenotype. The tumor morphology is altered and appears to be less differentiated. Additionally, we see a significant increase in the number of tumor cells expressing Zeb1 and a decrease in E-cadherin expression. We also find an increase in metastatic capacity in the absence of IL-23 in the tumor stroma. Single cell RNA sequencing of tumors injected orthotopically into IL-23 knockout mice reveals clusters of tumor cells with increases in EMT-associated genes such as Zeb1 and Vimentin and concurrent decreases in gastric identity genes. Overall, our findings indicate that IL-23 plays a role in suppressing an EMT-like phenotype in pancreatic cancer with one mechanism being through regulation of gastric lineage genes. Citation Format: Whitney Bell, Nancy Kren, Yan Wang, Yuliya Pylayeva-Gupta. Cytokine modulation can suppress an EMT-like phenotype in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C072.
Abstract C068: Isorhamnetin restricts cancer-associated fibroblasts (CAFs) phenotypic plasticity, poising them towards tumor-restraining myCAFs: Potential use of isorhamnetin as neoadjuvant in pancreatic ductal adenocarcinoma (PDAC)
Authors: Munkhzul Ganbold, Pakavarin Louphrasitthiphol, Yoshihiro Miyazaki, Tatsuya Oda, Kenichi Tominaga, Hiroko Isoda
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer due lack of early diagnosis and inherent refractory to traditional chemo- and even novel immune-therapies. PDAC is marked by its extensive desmoplastic stroma containing extracellular matrix (ECM), vasculature and most importantly cancer-associated fibroblasts (CAFs). CAFs that exist in heterogenous subtypes are responsible for shaping PDAC tumor microenvironment being the main source of: ECM deposition leading up to desmoplasia that hampers the efficacy of various therapeutics, as well as diverse cytokines and growth factors that promote the growth of cancer cells and the shift towards dedifferentiated and invasive phenotype and contribute towards immune suppressive microenvironment. Thus, modulating CAFs phenotype is an attractive mean to increase the efficacy of therapies targeting PDAC cells. Here we assessed the potential therapeutic benefits of Isorhamnetin, a flavonoid previously shown to exert anti-proliferative, anti-fibrotic and anti-inflammatory effect in various cancer types, to modulates PDAC microenvironment by characterizing Isorhamnetin effect on human PDAC-derived CAFs. Isorhamnetin inhibited CAFs proliferation, induced apoptosis, and cell cycle arrest by impairing mitochondrial health. Importantly, isorhamnetin attenuates the expression of inflammatory CAFs (iCAFs) signature including IL1A, IL6, LIF, CXCL1 and promotes phenotype shift towards myofibroblasts (myCAFs)-as evident in higher level of αSMA positive CAFs. Our results demonstrate antiproliferative effect of isorhamnetin on human PDAC-derived CAFs and a phenotype switch from iCAFs to myCAFs and warrant further investigation for its use in combinatorial therapy that target both the cancer and the tumor microenvironment as a whole. Citation Format: Munkhzul Ganbold, Pakavarin Louphrasitthiphol, Yoshihiro Miyazaki, Tatsuya Oda, Kenichi Tominaga, Hiroko Isoda. Isorhamnetin restricts cancer-associated fibroblasts (CAFs) phenotypic plasticity, poising them towards tumor-restraining myCAFs: Potential use of isorhamnetin as neoadjuvant in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C068.
Abstract B081: Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells
Authors: Sangeeta Choudhury, Neha Chopra, Kriti Jain, Poonam Yadav, Surinder P. Singh, Yashika Charla
Journal: Cancer Research (2022)

Abstract The knowledge of immunomodulatory and reparative properties of Mesenchymal Stem cells (MSCs) are rapidly advancing and could be best suited as a therapeutic option for inflammatory or adverse immunological conditions such as cancer. In the last decade, Mesenchymal stem cells have attracted significant attention because of their accessibility, tumor-oriented homing capacity and the transplantation feasibility. Until date, MSC-based therapy for pancreatic cancer has not been demonstrated. As per the current understanding of the potentials of MSCs in regenerative medicine, we hypothesized their inhibitory influence on pancreatic cancer cells. For experimentation purposes, we have used human Wharton’s jelly derived MSCs (hWJ-MSCs) and pancreatic cell line models. Our findings show that secretion of soluble biologically active factors from hWJ-MSCs (secretome) had a greater impact on induction of anergy and apoptosis of pancreatic tumor cells. The mechanistic approach directed to influence the tumor microenvironment appear to be two pronged: one, via modulation of tumor glycoproteins (MUC-1 and EpCAM) and second, via GSK3β/Stat3/HIF1-α axis. Treatment with calcitriol, an analogue of Vitamin D known to regulate cell cycle, cell differentiation ca also reduce side effects of chemo-drugs, one of the mainstay of therapy in pancreatic cancer. Yet, the potential mechanism to exert anti-cancer effect remains underexplored. We attempted to elicit the involvement of VitD in one of the crucial stem-cell related embryonic pathway, the Sonic Hedgehog (SHH) pathway. Our data showed enhanced apoptosis of calcitirol treated-pCSCs cells when treated with salinomycin (SHH inhibitor). Further combinatorial treatment with secretome + VitD decreased copy numbers of transcription factors C-myc, SMO, PTCH1, PTCH2, and hypoxia-induced factor (HIF1-α) demonstrating the potential mechanism of action. In conclusion, our experimental evidence postulates a potential mechanism by which VitD-analogue regulate sHH-mTOR axis and in combination with mesenchymal stem cell secretome can affect the proliferation and migratory (oncogenic) capabilities of pancreatic cancer stem cells. So, what next? Do we have the evidence to suggest secretome as a novel cell-free therapeutic candidate!! Citation Format: Sangeeta Choudhury, Neha Chopra, Kriti Jain, Poonam Yadav, Surinder P. Singh, Yashika Charla. Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B081.